Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

[Cholesterol crystal embolism mimicking a DRESS]. / Des embolies de cristaux de cholestérol mimant un DRESS.

INTRODUCTION: Clinical presentation of cholesterol crystal embolism (CCE) can be dermatologic when cholesterol crystals become lodged in small cutaneous arteries resulting in ischemia. We report a case of CCE with erythroderma misleading to a diagnostic of drug reaction with eosinophilia and systemic symptoms (DRESS). CASE REPORT: A 66 year-old woman presented with erythroderma few months after initiation of allopurinol. Acute renal failure was present with elevation in plasma creatinine concentration (523µmol/L) and hypereosinophilia (HE) (5666/mm3). Finally, the REGISCAR score helped to rule out DRESS diagnostic. Past blood-count tests were analyzed revealing chronic HE present before allopurinol initiation. Renal biopsy identified CCE. CONCLUSION: This case is the first to report a DRESS like presentation of CCE. Clinical findings are secondary to HE and not to occlusion of cutaneous arteries.

[Eruptive disseminated superficial porokeratosis associated with acute hepatitis E]. / Porokératose éruptive superficielle disséminée associée à une hépatite virale E aiguë.

BACKGROUND: Porokeratosis (PK) is a rare form of dermatosis characterized by a keratinization disorder of unknown etiology. Herein we describe the first case associated with hepatitis E virus infection. PATIENTS AND METHODS: A 69-year-old patient with colorectal cancer treated with radiation and chemotherapy followed by surgery in April 2017 presented two months later with jaundice associated with annular keratotic lesions of the skin with a raised border. Blood tests revealed elevated liver enzymes and hyperbilirubinemia. Viral hepatitis E was diagnosed based on serology and viral PCR after other aetiologies such as obstruction, auto-immune disease and other viruses (HAV, HBV, HCV, HSV, HIV, EBV and CMV) had been ruled out. A skin biopsy showed a cornoid lamella. Disseminated superficial porokeratosis associated with hepatitis E infection was then diagnosed. DISCUSSION: The mechanism of PK is unknown and probably involves a combination of different factors. PK has been described in patients with treatment-induced immunosuppression, solid cancer or AIDS, sometimes promoted by HCV viral infection, but never with concomitant HEV infection. A combination of immunosuppression induced by radio-chemotherapy and HEV infection could have prompted the development of PK in our patient. CONCLUSION: We report the first case of eruptive disseminated superficial porokeratosis associated with hepatitis E infection. The exact role of hepatitis E infection in the development of PK is still unclear.

[Amoxicillin-induced skin rash sparing a plaque of erythema migrans: Renbök phenomenon: Case report and literature review]. / Toxidermie à l'amoxicilline épargnant une plaque d'érythème migrant : phénomène de Renbök et revue de la littérature.

INTRODUCTION: Renbök phenomenon describes the inhibition of a lesion when a different one appears. We describe the first case of Renbök phenomenon occurring in a context of erythema migrans (EM) spared by an amoxicillin-induced skin rash and we also present a literature review. CASE REPORT: A 60-year-old patient was treated with amoxicillin for EM on the right knee and subsequently developed generalized erythema as a result of an antibiotic-induced skin rash, with sparing of the area previously affected by EM. Renbök phenomenon was diagnosed. DISCUSSION: In 1981, Cochran et al. first described a maculopapular drug reaction, which spared the sites of previous X irradiation for a tumor. Since then, nearly 40 cases have been reported, mostly describing patient with alopecia areata of the scalp with hair growth within plaques of psoriasis. One of the mechanisms suggested is a role played by cytokine cross-regulation in competition among distinct immune responses. CONCLUSION: We report the first case of Renbök phenomenon involving EM spared by a drug reaction. This phenomenon provides an insight into inflammatory response competition within a single patient.

Assessment of linear measurements of bone for implant sites in the presence of metallic artefacts using cone beam computed tomography and multislice computed tomography.

The objective was to evaluate the influence of dental metallic artefacts on implant sites using multislice and cone-beam computed tomography techniques. Ten dried human mandibles were scanned twice by each technique, with and without dental metallic artefacts. Metallic restorations were placed at the top of the alveolar ridge adjacent to the mental foramen region for the second scanning. Linear measurements (thickness and height) for each cross-section were performed by a single examiner using computer software. All mandibles were analysed at both the right and the left mental foramen regions. For the multislice technique, dental metallic artefact produced an increase of 5% in bone thickness and a reduction of 6% in bone height; no significant differences (p>0.05) were detected when comparing measurements performed with and without metallic artefacts. With respect to the cone-beam technique, dental metallic artefact produced an increase of 6% in bone thickness and a reduction of 0.68% in bone height. No significant differences (p>0.05) were observed when comparing measurements performed with and without metallic artefacts. The presence of dental metallic artefacts did not alter the linear measurements obtained with both techniques, although its presence made the location of the alveolar bone crest more difficult.

Multiple sclerosis and solar exposure before the age of 15 years: case-control study in Cuba, Martinique and Sicily.

Few studies report a protective role of childhood solar exposure to multiple sclerosis. Our objective was to confirm the protective role of childhood solar exposure in multiple sclerosis in Cuba, Martinique and Sicily. This was a matched case- control study, and cases met Poser criteria for clinically, laboratory (definite, probable) multiple sclerosis. Controls were resident population, without neurological disorder, living close to cases (within 100 km), matched for sex, age (+/-5 years), residence before age 15. We recruited 551 subjects during a 1-year period (193 cases, Cuba n = 95, Sicily n = 50, Martinique n = 48; 358 controls). Some (89%) met definite clinical multiple sclerosis criteria (relapsing remitting form (with and without sequel) (74%), secondary progressive (21%), primary progressive (5%)). Odds ratios in a uni-variate analysis were: family history of multiple sclerosis (5.1) and autoimmune disorder (4.0); wearing shirt (3.5), hat (2.7), pants (2.4); sun exposure causing sunburn (1.8); sun exposure duration (1 h more/day; weekends 0.91, weekdays 0.86); bare-chested (0.6); water sports (0.2). Independent factors in the multivariate analysis were family history of multiple sclerosis (4.8 (1.50-15.10)), wearing pants under sunlight (1.9 (1.10-3.20)), sun exposure duration (1 h more/ day, weekdays 0.90 (0.85-0.98), weekends 0.93 (0.87-0.99)), water sports (0.23 (0.13-0.40)). We conclude that outdoor leisure activities in addition to sun exposure reports are associated with a reduced multiple sclerosis risk, with evidence of dose response.

An epidemiological study of familial neurocysticercosis in an endemic Mexican community.

Neurocysticercosis (NC) caused by Taenia solium is a frequent parasitic disease of the central nervous system. It is highly endemic in many developing countries, where many people are exposed but few become infected. Here, the relevance of age, gender, and genetic and exposure factors on NC susceptibility was studied in 649 inhabitants of a rural community of Mexico. Endemicity was confirmed by the high prevalence of pig cysticercosis (32.8%) and human seroprevalence (43.8%). Human NC cases were diagnosed by computerised tomography scans. A questionnaire to evaluate risk factors was applied and familial relationships between participants were registered. An overall NC frequency of 9.1% (59/649) was found. NC frequency increased with age but did not associate with gender. Most NC cases were asymptomatic. None of the evaluated risk factors were associated with NC. No familial aggregation was detected when studying all cases, although a significant relationship between mother and child in cases with multiple parasites was found. These findings point to the fact that human NC in high exposure conditions is not simply related to exposure factors and they do not support the participation of a major gene in single-cyst NC. Rather, our results point to a complex interaction of genetic and environmental factors involved in NC.

[Cognitive disorders in an Andean community located in a cysticercosis endemic zone of Ecuador]. / Troubles cognitifs dans une communauté andine d'Equateur vivant en zone d'endémie cysticerquienne.

Mini mental state tests (MMS) were administered to 227 adults over the age of 40 years living in an Ecuadorian urban Andean community known to be an endemic zone for Taenia solium taeniasis and cysticercosis. The overall prevalence of cognitive impairment was 8.4% (19/227). The prevalence of cognitive impairment was 23.5% (8 cases) in adults over 75 years (n=34). The Hachinski ischemic score for vascular dementia was abnormal in 4 of the 19 adults (21%) exhibiting cognitive impairment. This survey highlighted a high prevalence of dementia in comparison with industrialised countries. Parasitic encephalopathy that was present in one out of five persons in this Andean community could play a part in early damage of cognitive function.

High prevalence of calcified silent neurocysticercosis in a rural village of Mexico.

Human neurocysticercosis (NC) is a parasitic disease caused by TAENIA SOLIUM when its larvae lodge in the central nervous system. NC prevalence estimates are obscured by the variable and often asymptomatic clinical picture. While infection depends on exposure, severity is possibly related with various host factors (immunity, genes and gender). This epidemiological study of cranial CT scans in an endemic rural community found that 9.1% of apparently healthy subjects had calcified lesions and were completely asymptomatic. Silent NC cases did not correlate with the exposure factors tested but showed family aggregation and higher rates of positive serology. Thus, NC prevalence may be higher than currently considered and host-related factors appear to be involved in infection and pathogenesis.

Dietary antioxidants, peroxidation and cardiovascular risks.

Most of the many epidemiological studies in the field strongly suggest that an equilibrated diet such as the so-called "mediterranean diet", is associated with protective effects against major diseases, and particularly, against cardiovascular risks. Since many reports also consider reactive oxygen species or free radical oxidations to be responsible for the accompanying disorders of most pathologies as well as for ageing, it is conceivable that natural plant metabolites such as polyphenols, are likely to play an important role in insuring this protection. Indeed, not only their presence, in particularly high amounts and varieties in foods of such a diet, but also, inter alia, their very potent antioxidant or radical scavenging properties, make polyphenols best accounting for the parodoxical part of the french paradox . Therefore, many efforts have been made to assess the mechanisms for such a cardiovascular disease protection. Whatever convincing were the polyphenols properties demonstrated by many in vitro experiments to support those theories, quite a great number of the results appeared somewhat contradictory when transposed to humans, in the in vivo situation. Some people totally refute this explanation, thinking that health benefits, as far as alcoholic beverages are concerned, originate from ethanol but also, with no doubt, some polyphenols even revealing to be pro-oxidants .

[Human African trypanosomiasis: present and future treatment ]. / La trypanosomose humaine africaine: propos sur le traitement actuel et les perspectives.

During his life General Lapeyssonnie coped with the hazards linked to the therapeutics of the human African trypanosomiasis (HAT), sometimes with passion and disappointment, sometimes with revolt and hope. Because of a lack of political and financial concern during the past decades, a real global policy against the disease and a drug research against HAT didn't emerge. Today, some changes seem to take place. They are the result of the frightening spread of the disease and of the moral obligation that forces pharmaceutical companies to intervene. Drug research needs to be increased. New drugs should present no toxicity and should be able to cross through the blood-brain barrier with efficient cerebrospinal fluid concentrations. Moreover, new drugs should be easy to synthesize, easy to use and at a low cost. Today, megazol is the only one product in preclinical development, which seems to reach each of these goals.

Neurocysticercosis: validity of ELISA after storage of whole blood and cerebrospinal fluid on paper.

Cysticercosis is an infestation of Cysticercus cellulosae. When it occurs in the brain, chronic neurological complications can ensue, most commonly seizures. Neurocysticercosis is usually diagnosed by neuroimaging, a technique not available in most endemic countries. Hence immunological tests are valuable for diagnosis and epidemiological surveys. We evaluated the suitability of paper for storing blood and cerebrospinal fluid (CSF) until subsequent testing by enzyme-linked immunosorbent assay (ELISA), by testing whole blood samples on filter paper from 305 patients and CSF samples from 117 patients stored on ordinary white typing paper and on filter paper. Optimal preservation of biological samples is achieved when whole blood is stored on filter paper, CSF on white paper, and when samples are frozen within 1 week after collection. Our results could improve diagnostic capabilities and facilitate epidemiological surveys in endemic countries where immunodiagnostic tests cannot be rapidly performed because of inadequate laboratory infrastructure.

A phase II trial of weekly intravenous ranpirnase (Onconase), a novel ribonuclease in patients with metastatic kidney cancer.

Ranpirnase (Onconase) is the first ribonuclease to enter cancer clinical trials. In prior phase II trials, responses were seen in mesothelioma and other solid tumors. This phase II trial tested ranpirnase (480 microg/m2/w) in 14 patients with refractory advanced renal cell cancer. The median performance status was zero and the median age was 55. All patients had prior immunotherapy and three had prior chemotherapy. No responses were seen in 14 patients. The median survival from on study was 16 months (range two to 28 months). At this dose and schedule ranpirnase has minimal activity in metastatic renal cell cancer.

Parkinson's disease and environmental factors. Matched case-control study in the Limousin region, France.

The study included 140 patients with Parkinson's disease (PD) and 280 non-Parkinson age-matched controls to evaluate environmental risk factors associated with PD. The effect of exposure to environmental and dietary factors was determined using conditional logistic regression. This multivariate analysis showed that PD in first-degree relatives and tea drinking were the main risk factors for PD. Smoking appeared to be a protective factor. Exposure to toxic compounds was not a significant risk factor. Further research is needed to validate that tea consumption increases the risk of PD.

Inhibition by SR 59119A of isoprenaline-, forskolin- and VIP-induced relaxation of human isolated bronchi.

In the human isolated bronchus (HIB) it has been shown that beta(3)-adrenoceptor stimulation fails to induce relaxation of airway smooth muscle. It has however been reported in human ventricular endomyocardial biopsies that beta(3)-adrenoceptor stimulation induced a marked negative inotropic effect which could be linked to Gi protein activation. The aims of this study were: (1) to determine in HIB (internal diameter 1-2 mm) whether the selective beta(3)-adrenoceptor agonist SR 59119A (N[7-methoxy-1,2,3, 4-tetrahydronaphthalen-(2R)methyl]-(2R)-2-hydroxy-2-(3-chloroph eny l)e thanamine hydrochloride) was able to inhibit adenylate-cyclase-mediated airway smooth muscle relaxation induced by isoprenaline, forskolin or vasoactive intestinal peptide (VIP) and (2) to investigate the role of the Gi protein in this interaction. SR 59119A (0.1 microM and 1 microM) induced a shift to the right of concentration response curve for isoprenaline (-0. 15+/-0.06 and -0.54+/-0.21 log unit, P<0.05 and P<0.01 respectively), forskolin (-0.12+/-0.02 and -0.30+/-0.05 log unit, P<0.001), and VIP (-0.42+/-0.12 log unit, P<0.01 with SR59119A 10(-6)M). The inhibitory effect of SR 59119A was (1) abolished by an incubation of HIB with pertussis toxin (1 microg/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to inactivate the Gi protein and (2) increased after an incubation of HIB with the pro-inflammatory cytokine IL-1beta (10 ng/ml, during 15 h in Krebs-Henseleit solution, at 21 degrees C), which is known to up-regulate Gi protein expression. Our results suggest that the selective beta(3)-adrenoceptor agonist SR59119A might inhibit the cAMP-dependent relaxation of human isolated bronchus through Gi protein-mediated inhibition of adenylate cyclase.

Functional, biochemical and molecular biological evidence for a possible beta(3)-adrenoceptor in human near-term myometrium.

The possible existence of a beta(3)-adrenoceptor (beta(3)-AR) in human near-term myometrium was investigated by in vitro functional and biochemical studies and analysis of mRNA expression. SR 59119A and SR 59104A and CGP 12177 (two selective agonists and a partial agonist, respectively, of the beta(3)-AR), salbutamol and terbutaline (beta(2)-AR agonists) each produced a concentration-dependent relaxation of the myometrial spontaneous contractions. There were no differences in pD(2) values for the relaxing potencies of terbutaline, salbutamol, CGP 12177 and SR 59119A. The rank order for their relaxing efficacies was SR 59119A>SR 59104A>terbutaline approximately salbutamol approximately CGP 12177 (E(max)=52+/-7%, 42+/-12% and approximately 30% respectively). Propranolol, a beta(1)- and beta(2)-AR antagonist, and ICI 118551, a beta(2)-AR antagonist (both at 0.1 microM), did not affect the SR 59119A-induced relaxation whereas SR 59230A, a selective beta(3)-AR antagonist (1 microM), significantly reduced the maximal relaxing effect of SR 59119A. SR 59119A and salbutamol induced a significant increase in cyclic AMP levels that was antagonized by SR 59230A but not by propranolol for SR 59119A, and by propranolol but not by SR 59230A for salbutamol. The beta(3)-AR mRNA was positively expressed in myometrium preparations in a reverse transcription polymerase chain assay. The results presented provide the first evidence for the existence of the beta(3)-AR subtype in human near-term myometrium and suggest that the effects of SR 59119A might be mediated through an increase in cyclic AMP level.